Collagen stimulators and their use in the treatment of skin

ABSTRACT

Methods for preventing, ameliorating, or reducing dermatological signs of aging are provided which employ cosmetic composition comprising novel active agents that enhance collagen production in the skin.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of, and claims priority to, U.S.patent application Ser. No. 13/721,491 filed on Dec. 20, 2012, theentirety of which is incorporated by reference herein for all purposes.

FIELD OF INVENTION

1. Field of Invention

The present invention relates generally to compounds, cosmeticformulations, and methods of improving the aesthetic appearance andhealth of human skin. In particular, the invention relates to compoundsthat promote the production of pro-collagen, collagen, and/or elastin inhuman skin.

2. Background

Collagen is the body's major structural protein. It is composed of threeprotein chains wound together in a tight triple helix to form fibrils.The fibrils are cross-linked in the extracellular matrix to provide thestructural scaffolding surrounding cells that helps to support cellshape and differentiation. The mesh-like collagen network binds cellstogether and provides the supportive framework or environment in whichcells develop and function. The stimulation of collagen gives the skinits strength, durability, and smooth, plump appearance.

Collagen is created by fibroblasts, which are specialized skin cellslocated in the dermis, through a complex multistep process involving thehydroxylation of lysine residues in the nascent procollagen proteinstrands. The resultant hydroxylysyl groups aid in the formation of thetriple helix and serve as attachment sites for cross linking in theextracellular matrix. See, Van der Slot et al., 2003, J. Biol. Chem.,278:40967-40972; Walker et al., 2005, Matrix Biology, 23:515-523; Wu etal., 2006, Exp. Cell Res., 312:3485-3494. Thus, this modification iscritical for the stability of procollagen, the intermolecular crosslinking of collagen fibrils and ultimately the maintenance of the dermalmatrix.

There is a continuing need for agents that stimulate procollagen and/orcollagen production in human skin. It is therefore an object of theinvention to provide new compounds, cosmetic formulations thereof, andmethods for stimulating procollagen and/or collagen production in humanskin. It is a further object of the invention to provide methods forimproving the overall appearance of skin, including treating, reversing,reducing, forestalling and/or preventing signs of aging, such as skinwrinkles and fine lines, sagging skin, and/or thinning skin bystimulating procollagen and/or collagen production.

The foregoing discussion is presented solely to provide a betterunderstanding of the nature of the problems confronting the art andshould not be construed in any way as an admission as to prior art.

SUMMARY OF THE INVENTION

In accordance with the foregoing objectives and others, the presentinvention provides compounds and cosmetic formulations thereof thatimprove one or more signs of dermatological aging when topically appliedto human integuments (skin, lips, nails, hair, etc.), particularly skin.The compounds of the invention lead to increased pro-collagen and/orcollagen production within dermal fibroblasts and therefore will have abeneficial effect on reducing the appearance of aging on skin.

In one aspect of the invention, cosmetic compositions are provided forimproving the aesthetic appearance of human skin comprising acosmetically acceptable vehicle, and an effective amount of an activeagent that stimulates pro-collagen and/or collagen production in theskin. The compounds of the invention will have a structure according toFormula I(a):

Q represents a 3-6 membered heterocyclic ring, wherein L₁ and L₂ areindependently selected from a bond or a group ε₁-(L₃)_(l)-ε₂, where “l”is an integer from 0 to 4; where L₃ is selected from —CH₂—, —CHR*—,—C(R*)₂—, —CH—, —CR*—, or a bond; and ε₁ and ε₂ are independentlyselected from —N—, —NH—, —NR^(N)—, —O—, —S—, —(C═O)—, or a bond; Y isselected from —CH—, —CR*—, —CHR*—, —C(R*)₂—, —N—, —O—, —S—, —NR^(N)—, ora bond (i.e. absent);

Z₁ represents a bond, —CH₂—, or —(C═O)—;

Z₂ represents a bond, —O—, NH—, —NR^(N)—, —CH₂—, —CHR*—, —C(R*)₂—,—(CH₂)_(p)—, —(CH₂)_(p)—NH, or —(CH₂)_(p)—NR^(N)—, where p is an integerfrom 1-6;

X₁ represents —CH₂—, —CHR*—, —C(R*)₂—, —NH—, —NR^(N)—, —O—, or —S—;

X₂ and X₃ represents nitrogen, —CH—, or —CR*—;

R₁-R₅ are independently selected, at each occurrence, from a group R;wherein R is selected from hydrogen, —F; —Cl; —Br; —I; —OH, —OR*; —NH₂;—NHR*; —N(R*)₂; —N(R*)₃ ⁺; —N(R*)—OH; —N(→O)(R*)₂; —O—N(R*)₂;—N(R*)—O—R*; —N(R*)—N(R*)₂; —C═N—R*; —N═C(R*)₂; —C═N—N(R*)₂;—C(═NR*)—N(R*)₂; —SH; —SR*; —CN; —NC; —(C═O)—R*; —CHO; —CO₂H; —CO₂;—CO₂R*; —(C═O)—S—R*; —O—(C═O)—H; —O—(C═O)—R*; —S—(C═O)—R*; —(C═O)—NH₂;—(C═O)—N(R*)₂; —(C═O)—NHNH₂; —O—(C═O)—NHNH₂; —(C═S)—NH₂; —(C═S)—N(R*)₂;—N(R*)—CHO; —N(R*)—(C═O)—R*; —(C═NR)—O—R*; —O—(C═NR*)—R*, —SCN; —NCS;—NSO; —SSR*; —N(R*)—C(═O)—N(R*)₂; —N(R*)—C(═S)—N(R*)₂; —SO₂—R*;—O—S(═O)₂—R*; —S(═O)₂—OR*; —N(R*)—SO₂—R*; —SO₂—N(R*)₂; —O—SO₃;—O—S(═O)₂—OR*; —O—S(═O)—OR*; —O—S(═O)—R*; —S(═O)—OR*; —S(═O)—R*; —NO;—NO₂; —NO₃; —O—NO; —O—NO₂; —N₃; —N₂—R*; —N(C₂H₄); —Si(R*)₃; —CF₃;—O—CF₃; —PR*₂; —O—P(═O)(OR*)₂; —P(═O)(OR*)₂; perfluoroalkyl; analiphatic C₁-C₁₂ hydrocarbon radical; a C₁-C₁₂ aromatic hydrocarbonradical; or a C₁-C₁₂ heteroaryl radical; where R* is independently ateach occurrence hydrogen or a straight chained, branched, or cyclicC₁-C₂₀ hydrocarbon radical, which may be saturated, partially saturated,or aromatic, each of which may be optionally substituted with 1-6heteroatoms selected from nitrogen, oxygen, sulfur, or halogen;

R^(N) is hydrogen or a straight chained, branched, or cyclic saturated,partially saturated, or aromatic C₁-C₂₀ hydrocarbon radical, optionallysubstituted with 1-6 heteroatoms selected from nitrogen, oxygen, sulfur,or halogen; and cosmetically acceptable salts of the compounds ofFormula I(a).

In some embodiments of the compounds of Formula I(a), L₁ is —(CH₂)_(m)—,and/or L₂ is —(CH₂)_(n)—, wherein “m” and “n” are independently selectedfrom integers from 1-3; and Y is selected from —N—, —NR^(N)—, —S—, —O—,or a bond. In other embodiments, Q defines a heterocycle selected fromthe group consisting of aziridine, diaziridine, oxaziridine, azetidine,diazetidine, oxazetidine, pyrrolidine, oxazolidine, thiazolidine,imidazolidine, pyrazolidine, pyrrole, imidazole, pyrazole,1,3,4-triazole, 1,2,3-triazole, piperidine, 4-alkyl-piperidine,morpholino, piperazine, and thiomorpholine, each being optionallysubstituted with one or more groups R. For example, Q may be aheterocycle selected from the group consisting of pyrrolidine,piperidine, morpholino, and piperazine, each being optionallysubstituted with one or more groups R (e.g., methyl). In oneillustrative embodiment, ring Q is 4-methyl-piperidine.

In some embodiments of the compounds of Formula I(a), Z₁ is a bond(i.e., it is altogether absent) or —CH₂—; and Z₂ is a bond, —NH— or—CH₂—. In other embodiments of the compounds of Formula I(a), Z₁ is—CH₂—; and Z₂ is —CH₂—. In other embodiments of the compounds of FormulaI(a), X₁ may be —NH— or —NR^(N)—; and/or X₂ and X₃ may be nitrogen.

Typically (but not necessarily) R₁, R₄, and/or R₅ are hydrogen; and R₂and/or R₃ may be a group —OR*, where R* is C₁₋₆ alkyl. In oneimplementation, R₂ and/or R₃ are a group —OCH₃. In one illustrativeembodiment, Z₁ is —CH₂—; Z₂ is —CH₂—; X₁ is —NH—; and X₂ and X₃ are eachnitrogen.

In another aspect of the invention, cosmetic compositions are providedcomprising a compound having the structure of Formula I(b):

and salts (e.g., acid addition salts) thereof.

The compounds of Formulas I(a) and I(B) may be formulated incosmetically acceptable vehicles, which may comprises one or more of afilm forming polymer, a thickener, a pH adjuster, a preservative, anemulsifier, a gelling agent, an antioxidant, a fragrance, a colorant,and the like. The vehicle may comprise a water-in-oil, oil-in-water,silicone-in-water, or water-in-silicone emulsion and will typicallyfurther comprise an emulsifier. The effective amount of the compoundwill typically be from about 0.00001% to about 1% (more typically, from0.001% to about 0.5%) by weight of the composition. The formulations mayoptionally include a retinoid, for example retinoic acid, retinol,retinal, retinyl acetate, fatty acid esters of retinol, such as retinylpalmitate, to name a few.

In another aspect of the invention, a method is provided for improvingthe aesthetic appearance of human skin comprising topically applying toan area of the skin in need thereof a composition comprising aneffective amount of a compound of Formula I(a) or I(b), for a timesufficient to improve the aesthetic appearance of said human skin. Theaesthetic improvement of human skin may be an improvement of anyattribute or characteristic of skin, including without limitation:

-   -   (a) treatment, reduction, and/or prevention of fine lines or        wrinkles;    -   (b) reduction of skin pore size;    -   (c) improvement in skin thickness, plumpness, and/or tautness;    -   (d) improvement in skin smoothness, suppleness and/or softness;    -   (e) improvement in skin tone, radiance, and/or clarity;    -   (f) improvement in procollagen, and/or collagen production;    -   (g) improvement in maintenance and remodeling of elastin;    -   (h) improvement in skin texture and/or promotion of        retexturization;    -   (i) improvement in skin barrier repair and/or function;    -   (j) improvement in appearance of skin contours;    -   (k) restoration of skin luster and/or brightness;    -   (l) replenishment of essential nutrients and/or constituents in        the skin;    -   (m) improvement of skin appearance decreased by aging and/or        menopause;    -   (n) improvement in skin moisturization;    -   (o) increase in skin elasticity and/or resiliency;    -   (p) treatment, reduction, and/or prevention of skin sagging;    -   (q) improvement in skin firmness; and    -   (r) reduction of pigment spots and/or mottled skin; and    -   (s) improvement of optical properties of skin by light        diffraction or reflection.

In one embodiment of the invention, an inventive compound may beidentified as CAS #1107720-70-6.

In a related implementation, a method is provided for the treatment ofwrinkles and/or fine lines on the skin human skin (typically, skin ofthe face) comprising topically applying to an area of the skin in needthereof (e.g., applying to a wrinkle or fine line) a composition ofFormulas I(a) or I(b), for a time sufficient to improve the aestheticappearance of said human skin. The treatment may be a least once ortwice daily and may last for a period of at least four weeks, typicallyat least eight weeks or longer. The composition may optionally furthercomprise a retinoid and/or an alpha-hydroxy acid (e.g., glycolic acid)and/or a beta-hydroxy acid (e.g., salicylic acid) in amounts effectiveto improve the appearance of skin.

In a related aspect, methods are provided for enhancing the productionof collagen or pro-collagen in human skin comprising topically applyingto an area of the skin in need thereof (e.g., sagging skin, thinningskin, skin suffering from wrinkles and fine lines, etc.) a topicalcomposition comprising a cosmetically acceptable vehicle, and aneffective amount of a compound of Formulas I(a) or I(b), for a timesufficient to improve the appearance thereof. The treatment may be aleast once or twice daily and may last for a period of at least fourweeks, typically at least eight weeks or longer. The composition mayoptionally further comprise a retinoid and/or an alpha-hydroxy acid(e.g., glycolic acid) and/or a beta-hydroxy acid (e.g., salicylic acid)in amounts effective to improve the appearance of skin.

In yet another aspect of the invention, methods are provided forreducing the severity of, reducing the number of, or preventing orforestalling the onset of, wrinkles or fine lines on human skincomprising topically applying to an area of the skin in need thereof(e.g., wrinkled skin), an effective amount (e.g., 0.0001%-1% by weight,w/w) of a compound of Formulas I(a) or I(b) in combination with aneffective amount (e.g., 0.01%-5% by weight, w/w) of retinol and/or aneffective amount (e.g., 0.001%-5% by weight, w/w) of an alpha-hydroxyacid (e.g., glycolic acid) and/or a beta-hydroxy acid (e.g., salicylicacid). The treatment may be a least once or twice daily and may last fora period of at least four weeks, typically at least eight weeks orlonger.

Further aspects, features and advantages of the present invention willbe better appreciated upon a reading of the following detaileddescription of the invention and claims.

DETAILED DESCRIPTION OF THE INVENTION

Detailed embodiments of the present invention are disclosed herein;however, it is to be understood that the disclosed embodiments aremerely illustrative of the invention that may be embodied in variousforms. In addition, each of the examples given in connection with thevarious embodiments of the invention are intended to be illustrative,and not restrictive. Therefore, specific structural and functionaldetails disclosed herein are not to be interpreted as limiting, butmerely as a representative basis for teaching one skilled in the art tovariously employ the present invention.

All terms used herein are intended to have their ordinary meaning unlessotherwise provided. By “cosmetically acceptable,” it is meant that aparticular component is generally regarding as safe and non-toxic at thelevels employed. The term “prevent,” as used herein, includes delayingthe onset of or progression of a particular sign of skin aging. The term“thin skin” includes skin that becomes thinner with chronological agingas well as prematurely thinned skin, which may be caused, for example,by photo-aging. In one embodiment, the prematurely thinned skin has beendiagnosed as such by a clinician. The phrase “individual in needthereof” refers to a human that could benefit from improved dermalappearance or health, including males or females. In some embodiments,the individual in need thereof is a female. The term “skin” includes,without limitation, the lips, skin of the face, hands, arms, neck,scalp, and chest. As used herein, the term “consisting essentially of”is intended to limit the invention to the specified materials or stepsand those that do not materially affect the basic and novelcharacteristics of the claimed invention, as understood from a readingof this specification.

The compounds of the invention improve the appearance of human skin.Without wishing to be bound by any particular theory, it is believedthat they do so by stimulating the production of pro-collagen and/orcollagen in the skin. The compounds of the invention generally have astructure according to Formula I(a):

Q represents a 3-6 membered heterocyclic ring, wherein L₁ and L₂ areindependently selected from a bond or a group ε₁-(L₃)_(l)-ε₂, where “l”is an integer from 0 to 4 (including 0, 1, 2, 3, and 4); where L₃ isselected from —CH₂—, —CHR*—, —C(R*)₂—, —CH—, —CR*—, or a bond; and ε₁and ε₂ are independently selected from —N—, —NH—, —NR^(N)—, —O—, —S—,—(C═O)—, or a bond; and in one embodiment, L₃ is —CH₂— and l is aninteger 1, 2, or 3, including an embodiment where L₃ is —CH₂— where l is2 and ε₁ and ε₂ are both a bond (i.e., absent) such that the groups L₁and/or L₂ have the form —CH₂—CH₂—; and in a particular embodiment, L₁and L₂ both have the form —CH₂—CH₂—, although any of the hydrogens inthe etheylene radical may be optionally substituted with groups R (e.g.,with methyl, etc.);

Y is selected from —CH—, —CR*—, —CHR*—, —C(R*)₂—, —N—, —O—, —S—,—NR^(N)—, or a bond (i.e., absent); but is typically —CH— or —CR*—,where R* is as defined above, with special mention being made of loweralkyl (i.e., methyl, ethyl, propyl, isopropyl, butyl, etc.).

Z₁ represents a bond, —CH₂—, or —(C═O)—; and is typically (but notnecessarily) —CH₂—; Z₂ represents a bond, —O—, NH—, —NR^(N)—, —CH₂—,—CHR*—, —C(R*)₂—, —(CH₂)_(p)—, —(CH₂)_(p)—NH, or —(CH₂)_(p)—NR^(N)—,where p is an integer from 1-6; and is typically (but not necessarily)—CH₂—. In one embodiment, Z₁ and Z₂ together form —CH₂—CH₂—, althoughany of the hydrogens in the etheylene radical may be optionallysubstituted with groups R (e.g., with methyl, etc.);

X₁ represents —CH₂—, —CHR*—, —C(R*)₂—, —NH—, —NR^(N)—, —O—, or —S—; andin some embodiments, X₁ represents —NH— or —NR^(N)—, where R^(N) is asdefined above, with special mention being made of lower alkyl (i.e.,methyl, ethyl, propyl, isopropyl, butyl, etc.). X₂ and X₃ may beindependently selected from nitrogen atoms, —CH—, and —CR*—. In oneembodiment, X₂ and/or X₃ are nitrogen atoms.

R₁-R₅ are independently selected, at each occurrence, from a group R;wherein R is selected from hydrogen, —F; —Cl; —Br; —I; —OH, —OR*; —NH₂;—NHR*; —N(R*)₂; —N(R*)₃; —N(R*)—OH; —N(→O)(R*)₂; —O—N(R*)₂; —N(R*)—O—R*;—N(R*)—N(R*)₂; —C═N—R*; —N═C(R*)₂; —C═N—N(R*)₂; —C(═NR*)—N(R*)₂; —SH;—SR*; —CN; —NC; —(C═O)—R*; —CHO; —CO₂H; —CO₂; —CO₂R*; —(C═O)—S—R*;—O—(C═O)—H; —O—(C═O)—R*; —S—(C═O)—R*; —(C═O)—NH₂; —(C═O)—N(R*)₂;—(C═O)—NHNH₂; —O—(C═O)—NHNH₂; —(C═S)—NH₂; —(C═S)—N(R*)₂; —N(R*)—CHO;—N(R*)—(C═O)—R*; —(C═NR)—O—R*; —O—(C═NR*)—R*, —SCN; —NCS; —NSO; —SSR*;—N(R*)—C(═O)—N(R*)₂; —N(R*)—C(═S)—N(R*)₂; —SO₂—R*; —O—S(═O)₂—R*;—S(═O)₂—OR*; —N(R*)—SO₂—R*; —SO₂—N(R*)₂; —O—SO₃; —O—S(═O)₂—OR*;—O—S(═O)—OR*; —O—S(═O)—R*; —S(═O)—OR*; —S(═O)—R*; —NO; —NO₂; —NO₃;—O—NO; —O—NO₂; —N₃; —N₂—R*; —N(C₂H₄); —Si(R*)₃; —CF₃; —O—CF₃; —PR*₂;—O—P(═O)(OR*)₂; —P(═O)(OR*)₂; perfluoroalkyl; an aliphatic C₁-C₁₂hydrocarbon radical; a C₁-C₁₂ aromatic hydrocarbon radical; or a C₁-C₁₂heteroaryl radical; where R* is independently at each occurrencehydrogen or a straight chained, branched, or cyclic C₁-C₂₀ hydrocarbonradical, which may be saturated, partially saturated, or aromatic, eachof which may be optionally substituted with 1-6 heteroatoms selectedfrom nitrogen, oxygen, sulfur, or halogen;

R^(N) is hydrogen or a straight chained, branched, or cyclic saturated,partially saturated, or aromatic C₁-C₂₀ hydrocarbon radical, optionallysubstituted with 1-6 heteroatoms selected from nitrogen, oxygen, sulfur,or halogen; and cosmetically acceptable salts of the compounds ofFormula I(a).

In some embodiments of the compounds of Formula I(a), L₁ is —(CH₂)_(m)—,and/or L₂ is —(CH₂)_(n)—, wherein “m” and “n” are independently selectedfrom integers from 1-3; and Y is selected from —N—, —NR^(N)—, —S—, —O—,or a bond. In other embodiments, Q defines a heterocycle selected fromthe group consisting of aziridine, diaziridine, oxaziridine, azetidine,diazetidine, oxazetidine, pyrrolidine, oxazolidine, thiazolidine,imidazolidine, pyrazolidine, pyrrole, imidazole, pyrazole,1,3,4-triazole, 1,2,3-triazole, piperidine, 4-alkyl-piperidine,morpholino, piperazine, and thiomorpholine, each being optionallysubstituted with one or more groups R. For example, Q may be aheterocycle selected from the group consisting of pyrrolidine,piperidine, morpholino, and piperazine, each being optionallysubstituted with one or more groups R (e.g., methyl). In oneillustrative embodiment, ring Q is 4-methyl-piperidine.

In some embodiments of the compounds of Formula I(a), Z₁ is a bond(i.e., it is altogether absent) or —CH₂—; and Z₂ is a bond, —NH— or—CH₂—. In other embodiments of the compounds of Formula I(a), Z₁ is—CH₂—; and Z₂ is —CH₂—. In other embodiments of the compounds of FormulaI(a), X₁ may be —NH— or —NR^(N)—; and/or X₂ and/or X₃ may be nitrogen.Typically (but not necessarily) R₁, R₄, and/or R₅ are hydrogen; and R₂and/or R₃ may be a group —OR*, where R* is C₁₋₆ alkyl. In oneimplementation, R₂ and/or R₃ are a group —OCH₃. In one illustrativeembodiment, Z₁ is —CH₂—; Z₂ is —CH₂—; X₁ is —NH—; and X₂ and X₃ are eachnitrogen.

The invention embraces the use of cosmetically or pharmaceuticallyacceptable (e.g., non-toxic and/or non-irritating) salts of thecompounds of Formula I(a). Examples of the salts of the compounds in thepresent invention include salts with alkali metals such as sodium andpotassium; salts with alkaline-earth metals such as calcium andmagnesium; salts with amines such as monoethanolamine; salts withinorganic acids such as hydrochloric acid and sulfuric acid; and saltswith organic acids such as citric acid and acetic acid. Special mentionmay be made of acid addition salts and in particular hydrochloridesalts.

In another aspect of the invention, cosmetic compositions are providedcomprising a compound (or salt thereof) having the structure I(b):

The compounds of Formula I(a) or I(b) may be racemic or may comprise andenantiomeric excess of either the R or S enantiomer at the stereocenterdefined by the point of attachment of the methyl group to thepiperidinyl ring. In some embodiments, the compound comprise andenantiomeric excess of at least about 90% of the R enantiomer; in otherembodiments the compound comprises an enantiomeric excess of at leastabout 90% of the S enantiomer. In some embodiments, the methyl group onthe piperidinyl ring may be replaced by hydrogen, trifluoromethyl,ethyl, methoxy, amino, trimethylamino, carboxy, or cyano groups.

The compounds of Formulas I(a) and I(b) may be formulated incosmetically acceptable vehicles, which may comprises one or more of afilm forming polymer, a thickener, a pH adjuster, a preservative, anemulsifier, a gelling agent, an antioxidant, a fragrance, a colorant,and the like. The vehicle may comprise a water-in-oil, oil-in-water,silicone-in-water, or water-in-silicone emulsion and will typicallyfurther comprise an emulsifier. The effective amount of the compoundwill typically be from about 0.00001% to about 1% (more typically, from0.001% to about 0.5%) by weight of the composition. The formulations mayoptionally include a retinoid, for example retinoic acid, retinol,retinal, retinyl acetate, fatty acid ester of retinol, such as retinylpalmitate, to name a few.

In another aspect of the invention, a method is provided for improvingthe aesthetic appearance of human skin comprising topically applying toan area of the skin in need thereof a composition comprising aneffective amount of a compound of Formula I(a) or I(b), for a timesufficient to improve the aesthetic appearance of said human skin.

In a related implementation, a method is provided for the treatment ofwrinkles and/or fine lines on the skin human skin (typically, skin ofthe face) comprising topically applying to an area of the skin in needthereof (e.g., applying to a wrinkle or fine line) a composition ofFormulas I(a) or I(b), for a time sufficient to improve the aestheticappearance of said human skin. The treatment may be a least once ortwice daily and may last for a period of at least four weeks, typicallyat least eight weeks or longer. The composition may optionally furthercomprise a retinoid and/or an alpha-hydroxy acid (e.g., glycolic acid)and/or a beta-hydroxy acid (e.g., salicylic acid) in amounts effectiveto improve the appearance of skin.

In a related aspect, methods are provided for enhancing the productionof collagen or pro-collagen in human skin comprising topically applyingto an area of the skin in need thereof (e.g., sagging skin, thinningskin, skin suffering from wrinkles and fine lines, etc.) a topicalcomposition comprising a cosmetically acceptable vehicle, and aneffective amount of a compound of Formulas I(a) or I(b), for a timesufficient to improve the appearance thereof. The treatment may be aleast once or twice daily and may last for a period of at least fourweeks, typically at least eight weeks or longer. The composition mayoptionally further comprise a retinoid and/or an alpha-hydroxy acid(e.g., glycolic acid) and/or a beta-hydroxy acid (e.g., salicylic acid)in amounts effective to improve the appearance of skin.

In yet another aspect of the invention, methods are provided forreducing the severity of, reducing the number of, or preventing orforestalling the onset of, wrinkles or fine lines on human skincomprising topically applying to an area of the skin in need thereof(e.g., wrinkled skin), an effective amount (e.g., 0.0001%-1% by weight,w/w) of a compound of Formulas I(a) or I(b) in combination with aneffective amount (e.g., 0.01%-5% by weight, w/w) of retinol and/or aneffective amount (e.g., 0.001%-5% by weight, w/w) of an alpha-hydroxyacid (e.g., glycolic acid) and/or a beta-hydroxy acid (e.g., salicylicacid). The treatment may be a least once or twice daily and may last fora period of at least four weeks, typically at least eight weeks orlonger.

The cosmetic compositions of this invention may further comprise aretinoid. Retinoids may be without limitation retinol (Vitamin A) andesters thereof, such as retinol palmitate, retinol acetate and retinolpropionate, and salts thereof, retinaldehyde, or retinoic acid (e.g.,all-trans or 13-cis) and derivatives thereof. The cosmetic compositionsof this invention may further comprise alpha-hydroxy acids, such asglycolic acid, or beta hydroxyl acids, such as salicylic acid.

The compositions are topically applied to the skin in effective amounts,by which is meant an amount sufficient to achieve a measurableimprovement in skin health or reduction in one or more dermatologicalsigns of aging with daily (once, twice, etc.) administration, typicallyfor a period of at least one week or more.

The aesthetic improvement of human skin may be an improvement of anyattribute or characteristic of skin (including reduction in one or moredermatological signs of aging), including without limitation:

-   -   (a) treatment, reduction, and/or prevention of fine lines or        wrinkles;    -   (b) reduction of skin pore size;    -   (c) improvement in skin thickness, plumpness, and/or tautness;    -   (d) improvement in skin smoothness, suppleness and/or softness;    -   (e) improvement in skin tone, radiance, and/or clarity;    -   (f) improvement in procollagen, and/or collagen production;    -   (g) improvement in maintenance and remodeling of elastin;    -   (h) improvement in skin texture and/or promotion of        retexturization;    -   (i) improvement in skin barrier repair and/or function;    -   (j) improvement in appearance of skin contours;    -   (k) restoration of skin luster and/or brightness;    -   (l) replenishment of essential nutrients and/or constituents in        the skin;    -   (m) improvement of skin appearance decreased by aging and/or        menopause;    -   (n) improvement in skin moisturization;    -   (o) increase in skin elasticity and/or resiliency;    -   (p) treatment, reduction, and/or prevention of skin sagging;    -   (q) improvement in skin firmness; and    -   (r) reduction of pigment spots and/or mottled skin; and    -   (s) improvement of optical properties of skin by light        diffraction or reflection.

In practice, the compositions of the invention may be applied, alone orin cosmetically acceptable vehicles, to skin in need of treatment. Thatis, skin which suffers from a deficiency or loss in any of the foregoingattributes or which would otherwise benefit from improvement in any ofthe foregoing skin attributes. The skin is typically treated once ortwice daily. The treatment may continue for a week, two weeks, fourweeks, eight weeks, six months or longer.

In one embodiment, the composition is intended for use as anon-therapeutic treatment. In another embodiment, the composition is anarticle intended to be rubbed, poured, sprinkled, or sprayed on,introduced into, or otherwise applied to the human body for cleansing,beautifying, promoting attractiveness, or altering the appearance, inaccordance with the US FD&C Act, §201(i).

In one embodiment the active agents are topically applied, in acosmetically acceptable vehicle, to skin suffering from fine linesand/or wrinkles to prevent, treat, and/or ameliorate the appearance ofthe fine lines and/or wrinkles in the skin. In this case, thecompositions are applied to skin in need of treatment, by which is meantskin already having wrinkles and/or fine lines or skin that is at riskof developing fine lines and/or wrinkles. The compositions may beapplied directly to the fine lines and/or wrinkles on the skin of theface, neck, lips, chest, and/or hands. The compositions or compounds canremediate signs of aging, including wrinkles and fine lines, byenhancing production of procollagen and/or collagen in skin.

In one embodiment, the invention is directed to a method of improvingthe aesthetic appearance of skin by increasing the production ofcollagen in the skin, the method comprising topically applying to anarea of the skin in need thereof an effective amount of a compoundaccording to Formula I(a), including the compound according to FormulaI(b), and in each case, topically acceptable acid addition saltsthereof.

The cosmetic compositions according to the invention can be formulatedin a variety of forms for topical application and will comprise fromabout 0.00001% to about 90% by weight of a compound of Formula I(a) orI(b), and typically will comprise such actives in an amount from about0.0001% to about 25% by weight, and more typically from about 0.001% toabout 10% by weight. In some embodiments, the compounds of Formula I(a)or I(b) will individually or collectively comprise from 0.01% to about5% by weight of the composition. When the cosmetic compositionsaccording to the invention are formulated in a liquid form, theytypically will be present at a concentration from about 0.001 μM toabout 50 μM, or from about 0.5 μM to about 10 μM, or from about 2.25 μMto about 10 μM.

The compositions can include a cosmetically acceptable vehicle. Suchvehicles may take the form of any known in the art suitable forapplication to skin and may include, but are not limited to, water;vegetable oils; mineral oils; esters such as octal palmitate, isopropylmyristate and isopropyl palmitate; ethers such as dicapryl ether anddimethyl isosorbide; alcohols such as ethanol and isopropanol; fattyalcohols such as cetyl alcohol, cetearyl alcohol, stearyl alcohol andbiphenyl alcohol; isoparaffins such as isooctane, isododecane and ishexadecane; silicone oils such as cyclomethicone, hydrocarbon oils suchas mineral oil, petrolatum, isoeicosane and polyisobutene; polyols suchas propylene glycol, glycerin, butylene glycol, pentylene glycol andhexylene glycol; liposomes; waxes; or any combinations or mixtures ofthe foregoing.

The vehicle may comprise an aqueous phase, an oil phase, an alcohol, asilicone phase or mixtures thereof and may be in the form of anemulsion. Non-limiting examples of suitable emulsions includewater-in-oil emulsions, oil-in-water emulsions, silicone-in-wateremulsions, water-in-silicone emulsions, glycerin-in-oil emulsions,wax-in-water emulsions, water-oil-water triple emulsions or the like.The emulsion may include an emulsifier, such as a nonionic, anionic oramphoteric surfactant, or a gelling agent.

In one embodiment, the topical composition will have a pH range from 1to 8, with a pH in the range of from 2 to 7 being typical. In someembodiment, the composition will have a pH in the range of from 3.5 to5.5. Suitable pH adjusters such as citric acid and triethanolamine maybe added to bring the pH within the desired range. In one embodiment,the pH of the cosmetic formulation is maintained at or below about 4.0so as to enhance retinoid stability.

In one embodiment of the invention, the compositions may includeadditional skin actives, including but not limited to, retinoids,botanicals, keratolytic agents, desquamating agents, keratinocyteproliferation enhancers, collagenase inhibitors, elastase inhibitors,depigmenting agents, anti-inflammatory agents, steroids, anti-acneagents, antioxidants, and advanced glycation end-product (AGE)inhibitors.

The composition may comprise additional active ingredients havinganti-aging benefits, as it is contemplated that synergistic improvementsmay be obtained with such combinations. Exemplary anti-aging componentsinclude, without limitation, botanicals (e.g., Butea frondosa extract);phytol; thiodipropionic acid (TDPA) and esters thereof; retinoids (e.g.,9-cis retinoic acid, 13-cis retinoic acid, all-trans retinoic acid andderivatives thereof, phytanic acid, retinol (Vitamin A) and estersthereof, such as retinol palmitate, retinol acetate and retinolpropionate, and salts thereof and others); hydroxy acids (includingalpha-hydroxy acids and beta-hydroxy acids), salicylic acid and alkylsalicylates; exfoliating agents (e.g., glycolic acid,3,6,9-trioxaundecanedioic acid, etc.), estrogen synthetase stimulatingcompounds (e.g., caffeine and derivatives); compounds capable ofinhibiting 5 alpha-reductase activity (e.g., linolenic acid, linoleicacid, finasteride, and mixtures thereof); and barrier function enhancingagents (e.g., ceramides, glycerides, cholesterol and its esters,alpha-hydroxy and omega-hydroxy fatty acids and esters thereof, etc.),to name a few.

Exemplary retinoids include, without limitation, retinoic acid (e.g.,all-trans or 13-cis), and derivatives thereof, retinaldehyde, retinol(Vitamin A) and esters thereof, such as retinol palmitate, retinolacetate and retinol propionate, and salts thereof. Particular mentionmay be made of retinol. It is contemplated that combinations of thecompounds of Formula I(a) or I(b) with any of these retinoids willprovide enhanced or synergistic improvements to skin. The retinoids willtypically be included in amounts from about 0.0001% to about 5% byweight, more typically from about 0.01% to about 2.5% by weight, or fromabout 0.1% to about 1.0% by weight. Compositions according to thisembodiment may typically include an antioxidant such as ascorbic acidand/or BHT and/or a chelating agent such as EDTA or a salt thereof.

In another embodiment, the topical compositions of the present inventionmay also include one or more of the following: a skin penetrationenhancer; an emollient, such as isopropyl myristate, petrolatum,volatile or non-volatile silicones oils (e.g., methicone, dimethicone),ester oils, mineral oils, and fatty acid esters; a humectant, such asglycerin, hexylene glycol or caprylyl glycol; a skin plumper, such aspalmitoyl oligopeptide, collagen, collagen and/or glycosaminoglycan(GAG) enhancing agents; a sunscreen, such as avobenzone; an exfoliatingagent; and an antioxidant.

Suitable exfoliating agents include, for example, alpha-hydroxy acids,beta-hydroxy acids, oxa-acids, oxadiacids, and their derivatives such asesters, anhydrides and salts thereof. Suitable hydroxy acids include,for example, glycolic acid, lactic acid, malic acid, tartaric acid,citric acid, 2-hydroxyalkanoic acid, mandelic acid, salicylic acid andderivatives thereof. One exemplary exfoliating agent is glycolic acid.When present, the exfoliating agent may comprise from about 0.01% toabout 20% by weight of the composition.

Examples of antioxidants that may be used in the present compositionsinclude compounds having phenolic hydroxy functions, such as ascorbicacid and its derivatives/esters; beta-carotene; catechins; curcumin;ferulic acid derivatives (e.g., ethyl ferulate, sodium ferulate); gallicacid derivatives (e.g., propyl gallate); lycopene; reductic acid;rosmarinic acid; tannic acid; tetrahydrocurcumin; tocopherol and itsderivatives; uric acid; or any mixtures thereof. Other suitableantioxidants are those that have one or more thiol functions (—SH), ineither reduced or non-reduced form, such as glutathione, lipoic acid,thioglycolic acid, and other sulfhydryl compounds. The antioxidant maybe inorganic, such as bisulfites, metabisulfites, sulfites, or otherinorganic salts and acids containing sulfur. In one particularembodiment, the inventive compositions will include a combination ofretinol, TDPA or an ester thereof (notably, dilauryl thiodipropionicacid), and an alpha hydroxyl acid (glycolic acid) and/or beta hydroxylacid (salicylic acid). Compositions of the present invention maycomprise an antioxidant, which may comprise from about 0.001 wt % toabout 10 wt %, or from about 0.01 wt % to about 5 wt %, of the totalweight of the composition.

Other conventional additives include: vitamins, such as tocopherol andascorbic acid; vitamin derivatives such as ascorbyl monopalmitate;thickeners such as hydroxyalkyl cellulose; gelling agents; structuringagents; metal chelating agents such as EDTA or salts thereof; pigments;colorants; and pH adjusters. The composition may optionally compriseother components known to those skilled in the art including, but notlimited to, film formers, moisturizers, minerals, viscosity and/orrheology modifiers, anti-acne agents, insect repellents, skin coolingcompounds, skin protectants, lubricants, fragrances, preservatives,stabilizers, and mixtures thereof. In addition to the foregoing, thecosmetic compositions of the invention may contain any other compoundfor the treatment of skin disorders.

The composition may be formulated in a variety of product forms, suchas, for example, an emulsion, lotion, cream, serum, spray, aerosol,cake, ointment, essence, gel, paste, patch, pencil, towelette, mask,stick, foam, elixir, concentrate, and the like, particularly for topicaladministration. The composition is typically formulated as an emulsion,lotion, cream, ointment, serum or gel.

The invention provides a method for treating aging skin by topicallyapplying a composition comprising a collagen-stimulating compound ofFormula I(a) or I(b), typically in a cosmetically acceptable vehicle,over the affected area for a period of time sufficient to remediate,reverse, reduce, ameliorate, or prevent dermatological signs of aging.

Generally, the improvement in the condition and/or aesthetic appearanceis selected from the group consisting of: reducing dermatological signsof chronological aging, photo-aging, hormonal aging, and/or actinicaging; preventing and/or reducing the appearance of lines and/orwrinkles; reducing the noticeability of facial lines and wrinkles,facial wrinkles on the cheeks, forehead, perpendicular wrinkles betweenthe eyes, horizontal wrinkles above the eyes, and around the mouth,marionette lines, and particularly deep wrinkles or creases; improvingthe appearance of suborbital lines and/or periorbital lines; reducingthe appearance of crow's feet; rejuvenating and/or revitalizing skin,particularly aging skin; reducing skin fragility; preventing and/orreversing of loss of glycosaminoglycans and/or collagen; amelioratingthe effects of estrogen imbalance; preventing skin atrophy; preventing,reducing, and/or treating hyperpigmentation or hypopigmentation;minimizing skin discoloration; improving skin tone, radiance, clarityand/or tautness; preventing, reducing, and/or ameliorating skin sagging;improving skin firmness, plumpness, suppleness and/or softness;improving procollagen and/or collagen production; improving skin textureand/or promoting retexturization; improving skin barrier repair and/orfunction; improving the appearance of skin contours; restoring skinluster and/or brightness; minimizing dermatological signs of fatigueand/or stress; resisting environmental stress; replenishing ingredientsin the skin decreased by aging and/or menopause; improving communicationamong skin cells; increasing cell proliferation and/or multiplication;increasing skin cell metabolism decreased by aging and/or menopause;retarding cellular aging; improving skin moisturization; enhancing skinthickness; slowing or halting skin thinning; increasing skin elasticityand/or resiliency; enhancing exfoliation; improving microcirculation;decreasing and/or preventing cellulite formation; and any combinationsthereof. In some embodiments, each of the forgoing is associated withfemale skin.

In some embodiments, the compounds of Formulas I(a) or I(b) will be usedto reduce the severity of fine lines or wrinkles, often in combinationwith retinol. The composition will typically be applied to the skin one,two, or three times daily for as long as is necessary to achieve desiredresults. The treatment regiment may comprise daily application for atleast one week, at least two weeks, at least four weeks, at least eightweeks, or at least twelve weeks or more. Chronic treatment regimens arealso contemplated. The effect of a composition on the formation orappearance of fine lines and wrinkles can be evaluated qualitatively,e.g., by visual inspection, or quantitatively, e.g., by microscopic orcomputer assisted measurements of wrinkle morphology (e.g., the number,depth, length, area, volume and/or width of wrinkles per unit area ofskin). In one embodiment, the cosmetic compositions of the inventionwill be applied to the skin in an amount from about 0.001 to about 100mg/cm², more typically from about 0.01 to about 20 mg/cm², or from about0.1 to about 10 mg/cm².

It is also contemplated that the compositions of the invention will beuseful for treating thin skin by topically applying the composition tothin skin of an individual in need thereof. “Thin skin” is intended toinclude skin that is thinned due to chronological aging, menopause, orphoto-damage and skin that is thinning prematurely. In some embodiments,the treatment is for thin skin in men, whereas other embodiments treatthin skin in women, pre-menopausal or post-menopausal, as it is believedthat skin thins differently with age in men and women, and in particularin women at different stages of life.

The method of the invention may be employed prophylactically toforestall aging including in individuals that have not manifested signsof skin aging, most commonly in individuals under 25 years of age. Themethod may also reverse or treat signs of aging once manifested as iscommon in individuals over 25 years of age, or to slow the progressionof dermatological aging in such individuals.

In one embodiment, the compositions of the invention are applied tohuman skin to reduce sebum production or improve the appearance of skinaffected by cellulite, and/or reduce unwanted lipogenesis or increaselipolysis. In this embodiment, the compounds of Formulas I(a) or I(b)can be formulated in cosmetically acceptable vehicles (as describedherein) and may include one or more additional agents such as anti-acneingredients (e.g., salicylic acid, benzoyl peroxide and other peroxides,sulfur, retinoids, etc.) in the case of a facial composition, or, in thecase of a cellulite treatment, the formulation may comprise anyingredients suitable for treatment of cellulite, including withoutlimitation, perilla oil and other unsaturated fatty oils and omega-3fatty acids such as alpha-linolenic acid; caffeine; theophylline;xanthines; retinoids (e.g., retinol); and the like. A cellulitetreatment according to the invention will typically be applied topicallyto skin suffering from cellulite, including skin of the buttocks andthighs for a period of time sufficient to improve the appearancethereof, including for example, daily treatment for at least four weeks,at least eight weeks, at least twelve weeks, or longer.

In another embodiment, the compositions of the invention are applied tohuman skin for depigmentation, including to reduce areas of unwantedpigmentation, such as hyperpigmentation, including age spots andfreckles. In this embodiment, the compounds of Formulas I(a) or I(b) canbe formulated in cosmetically acceptable vehicles (as described herein)and may include one or more additional agents that combat pigmentationor hyperpigmentation, including tyrosinase inhibitors and/or melanosometransfer inhibitors. Special mention may be made of thiodipropionic acidand esters thereof (notably, di-lauryl esters); hydroquinone and themonobenzyl ether thereof; hydroquinone-beta-D-glucopyranoside; retinoids(e.g., retinoic acid); tretinoin; azelaic acid; Kojic acid(5-hydroxy-4-pyran-4-one-2-methyl); Mequinol (4-hydroxyanisole);Niacinamide; soy protein and other serine protease inhibitors; papermulberry extract; Glabridin (licorice extract); Arctostaphylos patulaand Arctostaphylos viscida extracts; Magnesium-L-ascorbyl-2-phosphate(MAP); 4-Isopropylcatechol; Aleosin; N-acetyl-4-S-cysteaminylphenol andN-propionyl-4-S-cysteaminylphenol; N-acetyl glucosamine; and Tranexamicacid (trans-4-aminomethylcyclohexanecarboxylic acid); to name a few.

In another embodiment, the compounds of Formulas I(a) and I(b) areintended for oral use, including for pharmaceutical use. Pharmaceuticalformulations will include pharmaceutically acceptable carriers (i.e.,diluents and excipients). The pharmaceutical compositions may beincluded in solid dosage forms, including compressed tablets andcapsules, or in liquid or powder forms. Pharmaceutical dosage forms willtypically include from about 0.5 mg to about 200 mg, or from about 1 mgto about 100 mg of the compound of Formulas I(a) and I(b). The dosageforms may be immediate release, in which case they will typicallycomprise a water-soluble or dispersible carrier such as microcrystallinecellulose, mannitol, hydroxypropyl methyl cellulose, PVP or the like, ormay be delayed, sustained, or modified release, in which case they maycomprise water-insoluble polymers such as cellulose ethers (e.g.,ethylcellulose), alone or in combination with water soluble ordispersible polymers, to regulate the rate of dissolution of the dosageform in the stomach.

EXAMPLES

The following example describes specific aspects of the invention toillustrate the invention but should not be construed as limiting theinvention, as the example merely provide specific methodology useful inthe understanding and practice of the invention and its various aspects.

Example 1

Stimulation of Collagen Production.

Cell Treatment: Normal Human dermal fibroblasts were grown in DMEM(Mediatech; cat. #: 15-013-CV) containing 10% Fetal Bovine Serum(Perbio; cat. #: SH30070.03), Penicillin/Streptomycin (Mediatech, Cat#30-001-C1), L-Glutamine (Mediatech; cat. #: 25-005-CI) at 37° C. and10% CO₂. Cells were stripped of serum overnight, followed by treatmentwith the compound of Formula I(b) (0.0005%) or vehicle (DMSO), in theabsence of serum for 48 hours.

Procollagen Assay: Procollagen levels in conditioned media weredetermined using Procollagen Type-I C-Peptide EIA Kit from Takara; cat.#MK101 as per manufacturer's suggestion. Reading was measured at 450 nmusing a spectrophotometer.

Results:

Human dermal fibroblasts treated with 0.0005% the compound of FormulaI(b) for 48 hours were analyzed by ELISA for expression levels ofpro-collagen. Cells treated with the compound of Formula I(b)demonstrated a significant increase in pro-collagen, relative tocontrol, vehicle treated cells. All values are statistically significantat p<0.05.

TABLE 1 Test Compound Procollagen Control 100% Formula I(b) (0.0005%)146%

Collagen is a key building block of the dermis, and production ofcollagen decline with ages, and thus contributes to wrinkle formation.The data in Table 1 shows that the compound of Formula I(b) stimulatesprocollagen production and therefore would be expected to help increaseskin's key building block, Collagen, and generate new collagen to helpfill wrinkles.

Additional Embodiments

1. A cosmetic composition for improving the aesthetic appearance ofhuman skin comprising a cosmetically acceptable vehicle, and aneffective amount of a compound according to Formula I(a):

wherein,

-   Q represents a 3-6 membered heterocyclic ring, wherein L₁ and L₂ are    independently selected from a bond or a group ε₁-(L₃)_(l)-ε₂, where    “l” is an integer from 0 to 4; where L₃ is selected from —CH₂—,    —CHR*—, —C(R*)₂—, —CH—, —CR*—, or a bond; and ε₁ and ε₂ are    independently selected from —N—, —NH—, —NR^(N)—, —O—, —S—, —(C═O)—,    or a bond; Y is selected from —CH—, —CR*—, —CHR*—, —C(R*)₂—, —N—,    —O—, —S—, —NR^(N)—, or a bond (i.e. absent);-   Z₁ represents a bond, —CH₂—, or —(C═O)—;-   Z₂ represents a bond, —O—, NH—, —NR^(N)—, —CH₂—, —CHR*—, —C(R*)₂—,    —(CH₂)_(p)—, —(CH₂)_(p)—NH, or —(CH₂)_(p)—NR^(N)—, where p is an    integer from 1-6;-   X₁ represents —CH₂—, —CHR*—, —C(R*)₂—, —NH—, —NR^(N)—, —O—, or —S—;-   X₂ and X₃ represents nitrogen, —CH—, or —CR*—;-   R₁-R₅ are independently selected, at each occurrence, from a group    R; wherein R is selected from hydrogen, —F; —Cl; —Br; —I; —OH, —OR*;    —NH₂; —NHR*; —N(R*)₂; —N(R*)₃; —N(R*)—OH; —N(→O)(R*)₂; —O—N(R*)₂;    —N(R*)—O—R*; —N(R*)—N(R*)₂; —C═N—R*; —N═C(R*)₂; —C═N—N(R*)₂;    —C(═NR*)—N(R*)₂; —SH; —SR*; —CN; —NC; —(C═O)—R*; —CHO; —CO₂H; —CO₂;    —CO₂R*; —(C═O)—S—R*; —O—(C═O)—H; —O—(C═O)—R*; —S—(C═O)—R*;    —(C═O)—NH₂; —(C═O)—N(R*)₂; —(C═O)—NHNH₂; —O—(C═O)—NHNH₂; —(C═S)—NH₂;    —(C═S)—N(R*)₂; —N(R*)—CHO; —N(R*)—(C═O)—R*; —(C═NR)—O—R*;    —O—(C═NR*)—R*, —SCN; —NCS; —NSO; —SSR*; —N(R*)—C(═O)—N(R*)₂;    —N(R*)—C(═S)—N(R*)₂; —SO₂—R*; —O—S(═O)₂—R*; —S(═O)₂—OR*;    —N(R*)—SO₂—R*; —SO₂—N(R*)₂; —O—SO₃; —O—S(═O)₂—OR*; —O—S(═O)—OR*;    —O—S(═O)—R*; —S(═O)—OR*; —S(═O)—R*; —NO; —NO₂; —NO₃; —O—NO; —O—NO₂;    —N₃; —N₂—R*; —N(C₂H₄); —Si(R*)₃; —CF₃; —O—CF₃; —PR*₂;    —O—P(═O)(OR*)₂; —P(═O)(OR*)₂; perfluoroalkyl; an aliphatic C₁-C₁₂    hydrocarbon radical; a C₁-C₁₂ aromatic hydrocarbon radical; or a    C₁-C₁₂ heteroaryl radical; where R* is independently at each    occurrence hydrogen or a straight chained, branched, or cyclic    C₁-C₂₀ hydrocarbon radical, which may be saturated, partially    saturated, or aromatic, each of which may be optionally substituted    with 1-6 heteroatoms selected from nitrogen, oxygen, sulfur, or    halogen;-   R^(N) is hydrogen or a saturated, partially saturated, or aromatic    C₁-C₂₀ hydrocarbon radical, optionally substituted with 1-6    heteroatoms selected from nitrogen, oxygen, sulfur, or halogen; and    cosmetically acceptable salts thereof.

2. The cosmetic composition according to claim 1, wherein L₁ is—(CH₂)_(m)—, and L₂ is —(CH₂)_(n)—, wherein “m” and “n” areindependently selected from integers from 1-3; and Y is selected from—N—, —NR^(N)—, —S—, —O—, or a bond.

3. The cosmetic composition according to claim 2, wherein ring Q is aheterocycle selected from the group consisting of aziridine,diaziridine, oxaziridine, azetidine, diazetidine, oxazetidine,pyrrolidine, oxazolidine, thiazolidine, imidazolidine, pyrazolidine,pyrrole, imidazole, pyrazole, 1,3,4-triazole, 1,2,3-triazole,piperidine, 4-alkyl-piperidine, morpholino, piperazine, andthiomorpholine, each being optionally substituted with one or moregroups R.

4. The cosmetic composition according to claim 3, wherein ring Q is aheterocycle selected from the group consisting of pyrrolidine,piperidine, morpholino, and piperazine, each being optionallysubstituted with one or more groups R.

5. The cosmetic composition according to claim 4, wherein ring Q is4-methyl-piperidine.

6. The cosmetic composition according to claim 1, wherein Z₁ is —CH₂—and Z₂ is —NH— or —CH₂—.

7. The cosmetic composition according to claim 1, wherein X₁ is —NH— or—NR^(N)—.

8. The cosmetic composition according to claim 1, wherein X₂ and X₃ arenitrogen.

9. The cosmetic composition according to claim 1, wherein R₁, R₄, and R₅are hydrogen.

10. The composition according to claim 1, wherein R₂ and/or R₃ are agroup —OR*, where R* is C₁₋₆ alkyl.

11. The composition according to claim 9, wherein R₂ and R₃ are a group—OCH₃.

12. The composition according to claim 4, wherein Z₁ is —CH₂—; Z₂ is—CH₂—; X₁ is —NH—; and X₂ and X₃ are each nitrogen.

13. The composition according to claim 1, wherein the compound accordingto Formula I(a) has the structure of Formula I(b):

and cosmetically acceptable salts thereof.

14. The composition according to claim 1, wherein said cosmeticallyacceptable vehicle comprises one or more of a film forming polymer, athickener, a pH adjuster, a preservative, an emulsifier, a gellingagent, an antioxidant, a fragrance, and a colorant.

15. The composition according to claim 1, wherein said cosmeticallyacceptable vehicle comprises a water-in-oil or oil-in-water emulsion andfurther comprises an emulsifier.

16. The composition according to claim 1, wherein said effective amountcomprises from about 0.00001% to about 1% by weight of said composition.

17. The composition according to claim 1, further comprising a retinoidselected from the group consisting of retinoic acid, retinol, retinal,retinyl acetate, and retinyl palmitate.

18. A method for improving the aesthetic appearance of human skincomprising topically applying to an area of the skin in need thereof acomposition according to claim 1, for a time sufficient to improve theaesthetic appearance of said human skin.

19. The method according to claim 18, wherein said aesthetic improvementof said human skin is selected from the group consisting of:

-   -   (a) treatment, reduction, and/or prevention of fine lines or        wrinkles;    -   (b) reduction of skin pore size;    -   (c) improvement in skin thickness, plumpness, and/or tautness;    -   (d) improvement in skin smoothness, suppleness and/or softness;    -   (e) improvement in skin tone, radiance, and/or clarity;    -   (f) improvement in procollagen, and/or collagen production;    -   (g) improvement in maintenance and remodeling of elastin;    -   (h) improvement in skin texture and/or promotion of        retexturization;    -   (i) improvement in skin barrier repair and/or function;    -   (j) improvement in appearance of skin contours;    -   (k) restoration of skin luster and/or brightness;    -   (l) replenishment of essential nutrients and/or constituents in        the skin;    -   (m) improvement of skin appearance decreased by aging and/or        menopause;    -   (n) improvement in skin moisturization;    -   (o) increase in skin elasticity and/or resiliency;    -   (p) treatment, reduction, and/or prevention of skin sagging;    -   (q) improvement in skin firmness; and    -   (r) reduction of pigment spots and/or mottled skin; and    -   (s) improvement of optical properties of skin by light        diffraction or reflection.

20. A method for improving the aesthetic appearance of human skincomprising topically applying to an area of the skin in need thereof acomposition according to claim 1, for a time sufficient to improve theaesthetic appearance of said human skin.

21. The method according to claim 20, wherein said aesthetic improvementof said skin is the treatment of wrinkles and/or fine lines on the skin,and wherein said method comprises topically applying the composition toaffected skin of an individual in need thereof, at least once daily fora period of at least four weeks.

22. The method according to claim 20, wherein said aesthetic improvementof said skin is the treatment of wrinkles and/or fine lines on the skin,and wherein said method comprises topically applying the composition toaffected skin of an individual in need thereof, at least once daily fora period of at least eight weeks.

23. A method for improving the aesthetic appearance of human skincomprising topically applying to an area of the skin in need thereof atopical composition comprising a cosmetically acceptable vehicle and aneffective amount of a compound having the structure of Formula I(b):

and cosmetically acceptable salts thereof, for a time sufficient toimprove the aesthetic appearance of said human skin.

24. The method according to claim 23, wherein said aesthetic improvementof said human skin is selected from the group consisting of:

-   -   (a) treatment, reduction, and/or prevention of fine lines or        wrinkles;    -   (b) reduction of skin pore size;    -   (c) improvement in skin thickness, plumpness, and/or tautness;    -   (d) improvement in skin smoothness, suppleness and/or softness;    -   (e) improvement in skin tone, radiance, and/or clarity;    -   (f) improvement in procollagen, and/or collagen production;    -   (g) improvement in maintenance and remodeling of elastin;    -   (h) improvement in skin texture and/or promotion of        retexturization;    -   (i) improvement in skin barrier repair and/or function;    -   (j) improvement in appearance of skin contours;    -   (k) restoration of skin luster and/or brightness;    -   (l) replenishment of essential nutrients and/or constituents in        the skin;    -   (m) improvement of skin appearance decreased by aging and/or        menopause;    -   (n) improvement in skin moisturization;    -   (o) increase in skin elasticity and/or resiliency;    -   (p) treatment, reduction, and/or prevention of skin sagging;    -   (q) improvement in skin firmness; and    -   (r) reduction of pigment spots and/or mottled skin; and    -   (s) improvement of optical properties of skin by light        diffraction or reflection.

25. The method according to claim 24, wherein said aesthetic improvementof said skin is the treatment of wrinkles and/or fine lines on the skin,and wherein said method comprises topically applying the composition toaffected skin of an individual in need thereof, at least once daily fora period of at least four weeks.

26. The method according to claim 25, wherein said composition istopically applied to affected skin of an individual in need thereof atleast once daily for a period of at least eight weeks.

27. The method according to claim 23, wherein said composition furthercomprises a retinoid.

28. The method according to claim 23, wherein said composition furthercomprises an alpha-hydroxy or beta-hydroxy acid.

29. The method according to claim 28, wherein said alpha-hydroxy acid isglycolic acid.

30. The method according to claim 28, wherein said beta-hydroxy acid issalicylic acid.

31. A method for enhancing the production of collagen in human skincomprising topically applying to an area of the skin in need thereof atopical composition comprising a cosmetically acceptable vehicle, and aneffective amount of a compound having the structure of Formula I(b):

and cosmetically acceptable salts thereof.

32. The method according to claim 29, wherein said composition furthercomprises a retinoid.

33. The method according to claim 31, wherein said composition furthercomprises an alpha-hydroxy or beta-hydroxy acid.

34. The method according to claim 33, wherein said alpha-hydroxy acid isglycolic acid.

35. The method according to claim 33, wherein said beta-hydroxy acid issalicylic acid.

All references including patent applications and publications citedherein are incorporated herein by reference in their entirety and forall purposes to the same extent as if each individual publication orpatent or patent application was specifically and individually indicatedto be incorporated by reference in its entirety for all purposes. Manymodifications and variations of this invention can be made withoutdeparting from its spirit and scope, as will be apparent to thoseskilled in the art. The specific embodiments described herein areoffered by way of example only, and the invention is to be limited onlyby the terms of the appended claims, along with the full scope ofequivalents to which such claims are entitled.

The invention claimed is:
 1. A formulation comprising a compositionaccording to Formula I(a):

wherein, Q represents a 3-6 membered heterocyclic ring, wherein L₁ andL₂ are independently selected from a bond or a group ε₁-(L₃)_(l)-ε₂,where “l” is an integer from 0 to 4; where L₃ is selected from —CH₂—,—CHR*—, —C(R*)₂—, —CH—, —CR*—, or a bond; and ε₁ and ε₂ areindependently selected from —N—, —NH—, —NR^(N)—, —O—, —S—, —(C═O)—, or abond; Y is selected from —CH—, —CR*—, —CHR*—, —C(R*)₂—, —N—, —O—, —S—,—NR^(N)—, or a bond (i.e. absent); Z₁ represents a bond, —CH₂—, or—(C═O)—; Z₂ represents a bond, —O—, NH—, —NR^(N)—, —CH₂—, —CHR*—,—C(R*)₂—, —(CH₂)_(p)—, —(CH₂)_(p)—NH, or —(CH₂)_(p)—NR^(N)—, where p isan integer from 1-6; X₁ represents —CH₂—, —CHR*—, —C(R*)₂—, —NH—,—NR^(N)—, —O—, or —S—; X₂ and X₃ represents nitrogen, —CH—, or —CR*—;R₁-R₅ are independently selected, at each occurrence, from a group R;wherein R is selected from hydrogen, —F; —Cl; —Br; —I; —OH, —OR*; —NH₂;—NHR*; —N(R*)₂; —N(R*)₃ ⁺; —N(R*)—OH; —N(→O)(R*)₂; —O—N(R*)₂;—N(R*)—O—R*; —N(R*)—N(R*)₂; —C═N—R*; —N═C(R*)₂; —C═N—N(R*)₂;—C(═NR*)—N(R*)₂; —SH; —SR*; —CN; —NC; —(C═O)—R*; —CHO; —CO₂H; —CO₂ ⁻;—CO₂R*; —(C═O)—S—R*; —O—(C═O)—H; —O—(C═O)—R*; —S—(C═O)—R*; —(C═O)—NH₂;—(C═O)—N(R*)₂; —(C═O)—NHNH₂; —O—(C═O)—NHNH₂; —(C═S)—NH₂; —(C═S)—N(R*)₂;—N(R*)—CHO; —N(R*)—(C═O)—R*; —(C═NR)—O—R*; —O—(C═NR*)—R*, —SCN; —NCS;—NSO; —SSR*; —N(R*)—C(═O)—N(R*)₂; —N(R*)—C(═S)—N(R*)₂; —SO₂—R*;—O—S(═O)₂—R*; —S(═O)₂—OR*; —N(R*)—SO₂—R*; —SO₂—N(R*)₂; —O—SO₃ ⁻;—O—S(═O)₂—OR*; —O—S(═O)—OR*; —O—S(═O)—R*; —S(═O)—OR*; —S(═O)—R*; —NO;—NO₂; —NO₃; —O—NO; —O—NO₂; —N₃; —N₂—R*; —N(C₂H₄); —Si(R*)₃; —CF₃;—O—CF₃; —PR*₂; —O—P(═O)(OR*)₂; —P(═O)(OR*)₂; perfluoroalkyl; analiphatic C₁-C₁₂ hydrocarbon radical; a C₁-C₁₂ aromatic hydrocarbonradical; or a C₁-C₁₂ heteroaryl radical; where R* is independently ateach occurrence hydrogen or a straight chained, branched, or cyclicC₁-C₂₀ hydrocarbon radical, which may be saturated, partially saturated,or aromatic, each of which may be optionally substituted with 1-6heteroatoms selected from nitrogen, oxygen, sulfur, or halogen; R^(N) ishydrogen or a saturated, partially saturated, or aromatic C₁-C₂₀hydrocarbon radical, optionally substituted with 1-6 heteroatomsselected from nitrogen, oxygen, sulfur, or halogen and cosmeticallyacceptable salts thereof; and a cosmetically-acceptable vehicle.